Herbal composition phy906 and its use in chemotherapy

ABSTRACT

This invention provides herbal compositions useful for increasing the therapeutic index of chemotherapeutic compounds. This invention also provides methods useful for improving the quality of life of an individual undergoing chemotherapy. Furthermore, this invention improves the treatment of disease by increasing the therapeutic index of chemotherapy drugs by administering the herbal composition PHY906 to a mammal undergoing such chemotherapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit to U.S. Provisional Patent ApplicationSer. No. 60/901,310, the contents of which are herein incorporated byreference in their entirety for all purposes. This application is alsorelated to the following applications and patent: U.S. patentapplication Ser. No. 09/522,055 filed Mar. 9, 2000; InternationalApplication No. PCT/US2001/007353 filed Mar. 8, 2001; U.S. patentapplication Ser. No. 10/220,876 filed Dec. 30, 2002 and issued as U.S.Pat. No. 7,025,993 on Apr. 11, 2006; U.S. Provisional Patent ApplicationSer. No. 60/625,943 filed Nov. 9, 2004; U.S. patent application Ser. No.11/100,433 filed Apr. 7, 2005; and International Application No.PCT/US2005/040605 filed Nov. 9, 2005, the contents of which are hereinincorporated by reference in their entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to herbal compositions and the use of themfor enhancing the therapeutic effects of chemotherapeutic compounds.

BACKGROUND OF THE INVENTION

Cancer remains one of the major cause of death around the world.Specifically, cancer is the second overall cause of death in the UnitedStates. Gastrointestinal cancers, including colorectal, liver, andpancreatic cancers, are of particular concerns not only because of theirhigh incidence rates, but also because of their high mortality rate,especially in pancreatic and liver cancer patients (1-4). From years1992-1999, studies revealed that the five-year relative survival rate ofcolorectal cancer was 62.3% while that of liver cancer was 6.9% and 4.4%for pancreatic cancer. The median survival of liver cancer was 3.5 weeksto 6 months while it was 4 to 6 months for pancreatic cancer (3). Withonly very poor chemotherapeutic regimens available, pancreatic cancerhas the highest mortality rate among all cancers in the United States,with a less than 5% survival rate 5 years from diagnosis (3). Althoughseveral regimens are currently used in clinical trials forhepatocellular carcinoma, there is no FDA-approved chemotherapeuticagent available. The low survival rates for both pancreatic andhepatocellular cancers are attributed to many factors includingdiagnosis is difficult, the tumor growth is highly aggressive, surgicalremoval of tumor is of low probability, and the tumor has a high rate ofchemotherapy resistance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of PHY906 (500 mg/kg, bid, D1-4 and 8-11) ontumor growth in Sorafenib (30 mg/kg, po, bid, D1-14)-treated BDF-1 mousebearing mouse colon 38 tumors. Sorafenib (30 mg/kg) was given orallytwice a day for a consecutive 14 days. PHY906 (500 mg/kg) was givenorally 30 min before sorafenib twice a day on days 1-4 and days 8-11(N=5 in each group).

FIG. 2 shows the effect of PHY906 (500 mg/kg, bid, D1-4, 8-11 and 15-18)on tumor growth in Sorafenib (30 mg/kg, po, bid, D1-20)-treated nudemice bearing human HepG2 tumors. Sorafenib (30 mg/kg) was given orallytwice a day for a consecutive 20 days. PHY906 (500 mg/kg) was givenorally 30 min before sorafenib twice a day on days 1-4, 8-11 and 15-18(N=5 in each group).

FIG. 3 shows the impact of PHY906 and Sorafenib on blood vessels fromthe liver of NCr-nude mice bearing human HepG2 xenografts. Tissuesections were prepared from formalin-fixed, paraffin-embedded livercancer specimens. Immunohistochemical staining was done using specificantibodies against CD31 (brown) and nuclear DNA (blue).

FIG. 4 shows impact of PHY906 and Sorafenib on VEGF level from the liverof NCr-nude mice bearing human HepG2 xenografts. Tissue sections wereprepared from formalin-fixed, paraffin-embedded liver cancer specimens.Immunohistochemical staining was done using specific antibodies againstVEGF (brown) and nuclear DNA (blue)

FIG. 5 shows the impact of PHY906 and Sorafenib on HIF-1α level from theliver of NCr-nude mice bearing human HepG2 xenografts. Tissue sectionswere prepared from formalin-fixed, paraffin-embedded liver cancerspecimens. Immunohistochemical staining was done using specificantibodies against HIF-1α (brown) and nuclear DNA (blue).

FIG. 6 shows the effect of PHY906 on the tumor growth inCapecitabine-treated NCr-nude mice bearing human Panc-1 tumor.Capecitabine (720 mg/kg) was given orally twice a day on days 1-7, 15-21and 29-32 days. PHY906 was given orally 30 min before capecitabine twicea day on days 1-4, 8-11, 15-18, 22-25 and 29-32 at 500 mg/kg (N=5 ineach group)

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a composition comprising:i) a pharmaceutically acceptable carrier; ii) an herbal preparationcomprising Scutellaria, Glycyrrhiza, Ziziphus, and Paeonia; and iii) oneor more chemotherapeutic compounds.

In another aspect, the present invention provides a method of treating adisease in a mammal in need thereof comprising administering atherapeutically effective amount of a composition comprising: i) apharmaceutically acceptable carrier; ii) an herbal preparationcomprising Scutellaria, Glycyrrhiza. Ziziphus, and Paeonia; and iii) oneor more chemotherapeutic compounds.

In another aspect, the present invention provides a method of increasingthe therapeutic index of cancer therapeutic compounds for the treatmentof cancer by administering to a mammal in need thereof, atherapeutically effective amount of a composition comprising apharmaceutically acceptable carrier, and an herbal preparationcomprising Scutellaria, Glycyrrhiza, Ziziphus, and Paeonia.

In yet another aspect, the present invention provides a method ofrelieving side effects of a chemotherapeutic compound in a mammalcomprising administering a composition comprising: i) a pharmaceuticallyacceptable carrier; ii) an herbal preparation comprising Scutellaria,Glycyrrhiza, Ziziphus, and Paeonia; and iii) one or morechemotherapeutic compounds.

In yet another aspect, the present invention provides a method ofimproving the quality of life of a mammal undergoing chemotherapy whichcomprises administering a therapeutically effective amount of one ormore chemotherapeutic compounds and a composition comprising: i) apharmaceutically acceptable carrier; ii) an herbal preparationcomprising Scutellaria, Glycyrrhiza, Ziziphus, and Paeonia; and iii) oneor more chemotherapeutic compounds.

DETAILED DESCRIPTION OF THE INVENTION

Gemcitabine is the only clinically approved chemotherapeutic agent forpancreatic cancer; however, the response rate in patients to gemcitabineis only 6-11% and the overall survival time is generally 4-6 months.Gemcitabine is a nucleoside analog with two mechanisms of action,including the inhibition of ribonucleotide reductase, an enzyme thatconverts nucleotide diphosphate to deoxynucleotide triphosphate and thatis required for DNA synthesis and that competes with deoxycytidinetriphosphate as a fraudulent base in DNA synthesis (3,5-10). With thelow response and survival rates of gemcitabine monotherapy, severalgemcitabine-combination drug regimens have been tested clinically forimproving therapeutic efficacy. These trials include gemcitabine withother commonly used and FDA-approved anti-cancer drugs including CPT-11,capecitabine, and oxaliplatin (11-14). Unfortunately, no satisfactorycombination drug regimens have been discovered and an effective regimenfor pancreatic cancer is urgently needed.

Capecitabine (Xeloda), an oral fluoropyrimidine, is a rationallydesigned oral prodrug efficiently absorbed from the gastrointestinaltract and converted to 5-FU, preferentially in neoplastic tissues. Ithas been approved by the FDA as a first-line chemotherapy for thetreatment of colorectal and breast cancers with reduced toxicities(15-17). Capecitabine has also shown promising antitumor activity as asingle agent in pancreatic cancer (18) and liver cancer (19).

Hepatocellular carcinoma (HCC) is currently treated by surgicalprocedures and chemotherapy. Surgical removal and postoperativetherapies may improve the outlook for some patients. Unfortunately, thevast majority of patients with hepatocellular carcinoma will haveunresectable cancers. In late 2007, sorafenib became the firstFDA-approved chemotherapeutic agent for HCC. Published clinical studiesindicate significant anti-tumor effects (20,21). Oral multikinaseinhibitor sorafenib (BAY 43-9006) has a dual-action on Raf kinase andvascular endothelial growth factor. Sorafenib prevents tumor growth bycombining inhibition in tumor cell proliferation and tumor angiogenesis.Preclinical studies suggest that sorafenib may offer therapeuticbenefits in HCC by blocking Raf-1 signal transduction pathway.

Colorectal cancer has been reported to be the third most common cause ofdeath from cancer in the United States (22). Recently, the FDA approvedthe triple combination use of Oxaliplatin/5-FU/LV as the first-linetreatment for patients with advanced colorectal cancer. Oxaliplatin is asynthesized diaminocyclohexane platinum compound, which like cisplatin,causes platinum-DNA adduct formation and destroys the integrity of DNA(23). Other types of chemotherapeutic agents, such as 5-FU, CPT-11, arecommon chemotherapeutic agents used in the treatment of colorectalcancer. Unfortunately, severe diarrhea has been identified as one of thedose-limiting toxicities among patients treated with chemotherapy.

Our studies showed that PHY906, an herbal composition, not only reducedchemotherapy-induced toxicities, including body weight loss andmortality, but it also enhanced the antitumor efficacy of abroad-spectrum of anticancer agents including, but not limited toCPT-11, 5-FU, CPT-11/5-FU/LV, VP-16, L-OddC and oxaliplatin/5-FU/LV incolorectal cancer; sorafenib, capecitabine, thalidomide, and CPT-11 inliver cancer; and capecitabine, oxaliplatin, gemcitabine andgemcitabine/oxaliplatin in pancreatic cancer in vive animal models. Thepositive results from these preclinical studies demonstrate that PHY906can be used as an adjuvant for a broad-spectrum of different types ofchemotherapeutic agents in anti-cancer therapy. These chemotherapeuticagents include, but are not limit to, capecitabine and sorafenib. Thecancers include, but are not limited to, colorectal, liver, andpancreatic cancers. The methods of the present invention can be used toimprove the quality of life of patients including mammals underchemotherapy. Specifically, this invention relates to the dosing andscheduling of PHY906 in potentiating the therapeutic index of abroad-spectrum of cancer chemotherapeutic agents by the herbalcomposition PHY906.

In one embodiment, the present invention provides a compositioncomprising a pharmaceutically acceptable carrier, materials or chemicalsfrom a plant species of each of the following genera of herbs:Scutellaria, Glycyrrhiza, Ziziphus and Paeonia, and one or morechemotherapeutic compounds. In another embodiment, the materials orchemicals from a plant species is in a form of a herbal compositioncomprising Scutellaria, Glycyrrhiza, Ziziphus and Paeonia. In yetanother embodiment, the herbal composition consists essentially ofScutellaria, Glycyrrhiza, Ziziphus and Paeonia.

In one embodiment, the plant species comprise Scutellaria baicalensis,Glycyrrhiza uralensis, Ziziphusjujuba, and Paeonia lactiflora. Inanother embodiment of the invention one or more chemotherapeuticcompounds are cancer chemotherapeutics. In one embodiment of theinvention the cancer chemotherapeutics are selected from the groupconsisting of capecitabine, sorafenib, and a combination thereof.

In one embodiment of the invention, a therapeutically effective amountof a composition comprising a pharmaceutically acceptable carrier,materials or chemicals from a plant species of each of the followinggenera of herbs: Scutellaria, Glycyrrhiza, Ziziphus and Paeonia, and oneor more chemotherapeutic compounds is used to treat a disease in amammal in need thereof. In another embodiment, the materials orchemicals from a plant species is in a form of a herbal compositioncomprising Scutellaria, Glycyrrhiza, Ziziphus and Paeonia. In yetanother embodiment, the herbal composition consists essentially ofScutellaria, Glycyrrhiza, Ziziphus and Paeonia.

In one embodiment, the present invention provides a method of treating adisease in a mammal. The method comprises administering to the mammal inneed thereof a therapeutically effective amount of a compositioncomprising a pharmaceutically acceptable carrier, materials or chemicalsfrom a plant species of each of the following genera of herbs:Scutellaria, Glycyrrhiza, Ziziphus and Paeonia, and one or morechemotherapeutic compounds. In another embodiment, the materials orchemicals from a plant species is in a form of a herbal compositioncomprising Scutellaria, Glycyrrhiza, Ziziphus and Paeonia. In yetanother embodiment, the herbal composition consists essentially ofScutellaria, Glycyrrhiza, Ziziphus and Paeonia.

In one embodiment, the present invention provides a method of relievingthe side effects of a chemotherapeutic compound in a mammal. The methodcomprises administering to the mammal in need thereof a compositioncomprising a pharmaceutically acceptable carrier, materials or chemicalsfrom a plant species of each of the following genera of herbs:Scutellaria, Glycyrrhiza, Ziziphus and Paeonia, and one or morechemotherapeutic compounds.

In one embodiment of the invention, a composition comprising apharmaceutically acceptable carrier, materials or chemicals from a plantspecies of each of the following genera of herbs: Scutellaria,Glycyrrhiza, Ziziphus and Paeonia, and one or more chemotherapeuticcompounds is administered to a mammal to enhance the therapeuticeffectiveness of chemodierapeutic compound. In another embodiment, thematerials or chemicals from a plant species is in a form of a herbalcomposition comprising Scutellaria, Glycyrrhiza. Ziziphus and Paeonia.In yet another embodiment, the herbal composition consists essentiallyof Scutellaria, Glycyrrhiza, Ziziphus and Paeonia.

In one embodiment of the invention, a composition comprising apharmaceutically acceptable carrier, materials or chemicals from a plantspecies of each of the following genera of herbs: Scutellaria,Glycyrrhiza, Ziziphus and Paeonia, and one or more chemotherapeuticcompounds is administered to a mammal to enhance the antitumor activityof a chemotherapeutic compound. In another embodiment, the materials orchemicals from a plant species is in a form of a herbal compositioncomprising Scutellaria, Glycyrrhiza, Ziziphus and Paeonia. In yetanother embodiment, the herbal composition consists essentially ofScutellaria, Glycyrrhiza, Ziziphus and Paeonia.

In one embodiment of the invention, a therapeutically effective amountof a composition comprising a pharmaceutically acceptable carrier,materials or chemicals from a plant species of each of the followinggenera of herbs: Scutellaria, Glycyrrhiza, Ziziphus and Paeonia, and oneor more chemotherapeutic compounds is administered to a mammal to treattumors. In another embodiment, the materials or chemicals from a plantspecies is in a form of a herbal composition comprising Scutellaria,Glycyrrhiza, Ziziphus and Paeonia. In yet another embodiment, the herbalcomposition consists essentially of Scutellaria, Glycyrrhiza, Ziziphusand Paeonia.

In one embodiment of the invention, a composition comprising apharmaceutically acceptable carrier, materials or chemicals from a plantspecies of each of the following genera of herbs: Scutellaria,Glycyrrhiza, Ziziphus and Paeonia, and one or more chemotherapeuticcompounds is administered to a mammal to inhibit the growth of tumors inmammals. In another embodiment, the materials or chemicals from a plantspecies is in a form of a herbal composition comprising Scutellaria,Glycyrrhiza, Ziziphus and Paeonia. In yet another embodiment, the herbalcomposition consists essentially of Scutellaria, Glycyrrhiza, Ziziphusand Paeonia.

In one embodiment of the invention, a composition comprising apharmaceutically acceptable carrier, materials or chemicals from a plantspecies of each of the following genera of herbs: Scutellaria,Glycyrrhiza, Ziziphus and Paeonia, and one or more chemotherapeuticcompounds is used to inhibit the growth of tumors. In anotherembodiment, the materials or chemicals from a plant species is in a formof a herbal composition comprising Scutellaria, Glycyrrhiza, Ziziphusand Paeonia. In yet another embodiment, the herbal composition consistsessentially of Scutellaria, Glycyrrhiza, Ziziphus and Paeonia. In oneembodiment, the tumors are present in a mammal or in vitro cells.

In one embodiment, the present invention provides a method of improvingthe quality of life of a mammal undergoing chemotherapy. The methodcomprises administering a therapeutically effective amount of one ormore chemotherapeutic compounds and a composition comprising: i) apharmaceutically acceptable carrier; ii) materials or chemicals from aplant species of each of the following genera of herbs: Scutellaria,Glycyrrhiza, Ziziphus and Paeonia; and iii) one or more chemotherapeuticcompounds. In another embodiment, the materials or chemicals from aplant species is in a form of a herbal composition comprisingScutellaria. Glycyrrhiza, Ziziphus and Paeonia. In yet anotherembodiment, the herbal composition consists essentially of Scutellaria,Glycyrrhiza. Ziziphus and Paeonia. Preferably, the mammal as referencedherein is a human.

The above-referenced chemotherapeutic agents or compounds, genera ofherbs, and other terms and phrases have been described and defined withdetails in the following patent applications and patent: U.S. patentapplication Ser. No. 09/522,055 filed Mar. 9, 2000; InternationalApplication No. PCT/US2001/007353 filed Mar. 8, 2001; U.S. patentapplication Ser. No. 10/220,876 filed Dec. 30, 2002 and issued as U.S.Pat. No. 7,025,993 on Apr. 11, 2006; U.S. Provisional Patent ApplicationSer. No. 60/625,943 filed Nov. 9, 2004; U.S. patent application Ser. No.11/100,433 filed Apr. 7, 2005; and International Application No.PCT/US2005/040605 filed Nov. 9, 2005, the content of which are hereinincorporated by reference in their entirety for all purposes.

Examples Materials and Methods

Drug: Sorafenib (Nexavar) was purchased from Bayer HealthCare(Leverkusen, Germany). Capecitabine (Xeloda®, CAP) was purchased fromRoche Laboratories Inc. (Nutley, N.J.). The clinical drug substance ofPHY906 (PHY906-6, FDA 165542) with 10% excipient was prepared by Sun TenPharmaceutical, Inc. (Taipei, Taiwan). The PHY906 formula is composed offour herbs: Scutellariae baicalensis Georgi, Paeonia lactiflora Pall.,Ziziphus jujuba Mill and Glycyrrhiza uralensis Fisch., with a relativeweight ratio of 3:2:2:2.

Mice: Female BDF-1 mice with body weights between 16 and 20 g (4-6 weeksold) were purchased from Charles River Laboratories (Wilmington, Mass.).Male NCr athymic nude mice with body weights between 16 and 20 g (4-6weeks old) were purchased from Taconic Farms (Garmantown, N.Y.).

Preparation of Sorafenib solution: Sorafenib (200 mg/tablet) wasdissolved in 5% gum arabic as the vehicle. The final solution contains30 mg/ml of sorafenib.

Preparation of capecitabine solution from capecitabine tablet:Capecitabine (150 mg/tablet) was dissolved in 40 mM citrate buffer (pH6.0) containing 5% gum arabic as the vehicle. The final solutioncontains 36 mg/ml of capecitabine.

Preparation of herbal extract from dry powder: The preparation of theherbal extract followed SOP#HERB-001-PHY906. Briefly, one gram of PHY906dry powder, containing 10% starch excipient, was added to 10 ml of 80°C. H₂O and incubated at 80° C. for 30 minutes. The supernatant wasseparated from the debris by centrifugation (12000 rpm, 10 min) at roomtemperature. The concentration of PHY906 supernatant was calculated as90 mg/ml of PHY906 (1 g/10 ml×0.9), based on the dry weight of the drypowder. The herbal extract was stored at room temperature and usedwithin 24 hours. Any residual precipitant that occurred upon standingwas vortexed into a suspension and used to treat the animals.

Tumor cells: The human hepatocellular carcinoma HepG2, human PANC-1pancreatic cancer, and mouse Colon 38 colorectal cancer cell lines werepurchased from the American Type Culture Collection (Rockville, Md.).The HepG2 and Colon 38 cell lines were routinely grown in MEME mediawhile the PANC-1 cell line was grown in DMEM media, supplemented with10% fetal bovine serum (FBS). The cells were implanted into the leftflank of mice. Tumor transplantation from mice to mice was performedwhen the tumor reached 1500-2000 mm³.

Mouse tumor model: Tumor cells (5×10⁶ cells in 0.1 ml PBS) weretransplanted subcutaneously into the left flank of mice. After 14 days,tumor ranging in size from 300-500 mm³ was selected for drug studies.The length and width of the each tumor was measured with slidingcalipers. The tumor size was estimated according to the followingformula:

Tumor size(mm³)=length(mm)×width(mm)²/2.

The studies were conducted and the animals were maintained at the YaleAnimal Facility.

Antitumor activity of chemotherapeutic agents in the presence or absenceof PHY906: A total of 20 tumor-bearing mice were divided into 4 groups(N=5 mice/group):

-   -   1. Vehicle    -   2. PHY906    -   3. Chemotherapeutic agent    -   4. PHY906+Chemotherapeutic agent

The first day of drug treatment was defined as day 1. PHY906 (500 mg/kg,bid) was administrated orally to the mice 30 min before chemotherapeuticagents at the days indicated. Chemotherapeutic agents were given eitherintraperitoneally or orally at the dose and schedule indicated. Thetumor size, body weight, and mortality of the mice were monitored daily.Mice were sacrificed when the tumor size reached 10% of body weight.

Immunohistochemnistry: Formalin-fixed paraffin-embedded liver tissue wasfreshly cut into slices of 4 mm. The sections were mounted on Superfrostslides, dewaxed with xylene, and gradually hydrated. Antigen retrievalwas achieved by 0.05% citraconic anhydride buffer (pH 7.4) at 94° C. for1 h. The primary HIF-1α, CD31 or VEGF antibodies was diluted 1:75 usingTris-HCl buffer containing 1% BSA and 0.5% Tween-20. The primaryantibody was incubated at room temperature for 1 hour. As a negativecontrol, two slides were processed without primary antibody. Detectiontook place by the conventional labeled streptavidin-biotin method withalkaline phosphatase as the reporting enzyme according to themanufacturer's instructions. DAB (3,3′-diaminobenzidinetetrahydrochloride, purchased from Sigma-Aldrich, St Louis, Mo.) servedas chromogen. Afterwards, the slides were briefly counterstained withhematoxylin and aqueously mounted.

Statistical analysis and statistical power of the study (24): A randomeffects model was employed to analyze data from similar dosing animaltrials. The PROC MIXED procedure in SAS was used to take into accountthe correlation among observations collected from the same mouse.

The following model was used to analyze the longitudinal data:

y _(ijk) =μαt _(k)+β(I _(D) t _(k))+γ(I _(P) t _(k))+δ(I _(D) I _(P) t_(k))+e _(ijk),

where y_(ijk) is the relative tumor size of the jth individual with theith group (no treatment, drug alone. PHY906 alone, and drug+PHY906) atthe kth time point, t_(k) is the kth time point, α is the baseline timeeffect (no treatment group), I_(D) and I_(P) are indicator variables forhaving the drug treatment and the PHY906 treatment, β is thedrug-specific linear time effect. γ is the PHY906-specific linear timeeffect, is the drug-PHY906 synergistic linear time effect, and e_(ijk)is the residual (error) term. We assumed that the errors from differentindividuals are independent, and errors from the same individual atdifferent time points follow the autoregressive model, AR(1), to takeinto account the fact the observations from the same individual withinthe same treatment group are more correlated, and the responses fromcloser time points are more correlated within the same individual. ThePROC MIXED in SAS 8.01 was used to perform the statistical analysis.

Results (1) Sorafenib Effect of PHY906 in Antitumor Activity ofSorafenib in Murine Colon 38 Bearing BDF-1 Mice

To determine whether the combinational use of PHY906 and sorafenib inorder to improve anti-tumor activity of sorafenib. Sorafenib at dose of30 mg/kg (BID, D1-14), in combination with a fixed dose of PHY906 at 500mg/kg (BID, D1-4 and 8-1), were studied in BDF-1 mice bearing Colon 38murine colorectal cancer. As shown in FIGS. 1, PHY906 significantlyenhanced the antitumor activity of sorafenib in Colon 38 bearing mice.Indeed, the tumor growth was suppressed when mice received thecombination of PHY906 and sorafenib.

Effect of PHY906 in (a) Antitumor Activity, (b) Blood Vessels, (c) VEGFLevel and (d) HIF-1α of Sorafenib in Human HepG2 Xenografts

PHY906 (500 mg/kg, BID, D1-4, 8-11 and 15-18) was tested on theantitumor activity of sorafenib (30 mg/kg, BID, D1-20) in human HepG2bearing nude mice. As shown in FIG. 2, the combination of sorafenib andPHY906 shrank the tumor size approximately 60% after the first week ofcombination drug treatment while mice treated with sorafenib alone didnot have the shrinkage in tumor.

The immunohistochemical stainings on mouse liver indicate that theintegrity of tumor blood vessels are destroyed with the combinationtreatment of PHY906 and sorafenib, as shown in FIG. 3. The expressionsof VEGF and HIF-1α are suppressed by the combination treatment of PHY906and sorafenib, as shown in FIGS. 4 and 5, respectively. The data alsosuggests that the combination treatment of PHY906 and sorafenib affectsthe Fos/Juk transcription.

(2) Capecitabine Effect of PHY906 on the Antitumor Activity ofCapecitabine in Human Panc-1 Tumor-Bearing Nude Mice

PHY906 was previously found to potentiate the antitumor activity ofcapecitabine in human HepG2 xenografts. An experiment was thereforeconducted to study whether PHY906 could enhance the antitumor activityof capecitabine in human Panc-1 xenografts. Total 20 NCr nude micetransplanted with Panc-1 human pancreatic carcinoma cells were dividedinto 4 groups (N=5 mice/group): Group (A) vehicle control; Group (B)treated with PHY906 (500 mg/kg, bid, day 1-4, 8-11, 15-18, 22-25 and29-32); Group (C) treated with capecitabine (720 mg/kg, bid, day 1-7,15-21, and 29-32); and Group (D) treated with PHY906 (500 mg/kg, bid,days day 1-4, 8-11, 15-18, 22-25 and 29-32) plus capecitabine (720mg/kg, bid, day 1-7, 15-21, and 29-32). PHY906 was found to enhance theantitumor activity of capecitabine, as shown in FIG. 6. A similarobservation was found with lower doses of capecitabine (data not shown).

All applications, patent, and publications referenced herein areincorporated by reference to the same extent as if each individualapplication, patent, and publication was specifically and individuallyindicated to be incorporated by reference. Specifically, the disclosuresof WO 01/66123, WO 06/053049, U.S. Pat. No. 7,025,993, US 2005/0196473,and US 2003/0211180 are incorporated herein by reference in theirentirety for all purposes. Furthermore, the following references andtheir contents are herein incorporated by reference in their entirey forall purposes:

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1-17. (canceled)
 18. A composition for treating cancer in a mammal inneed thereof comprising a therapeutically effective amount of an herbalpreparation administering to the mammal in combination with sorafenib,wherein the herbal preparation comprises a therapeutically effectiveamount of Scutellaria, Glycyrrhiza, Ziziphus, and Paeonia; and atherapeutically effective amount of sorafenib, said composition beingformulated in pharmaceutical dosage form in combination with apharmaceutically acceptable carrier, additive and/or excipient thereof.19. The composition according to claim 18 wherein said herbalpreparation comprises Scutellaria baicalensis, Glycyrrhiza uralensis,Ziziphus jujuba, and Paeonia lactiflora.
 20. The composition accordingto claim 18 wherein said cancer is hepatocellular cancer.
 21. Thecomposition according to claim 19 wherein said cancer is hepatocellularcancer.
 22. The composition according to claim 18 wherein said cancer iscolorectal cancer.
 23. The composition according to claim 19 whereinsaid cancer is colorectal cancer.
 24. The composition according to claim18 wherein said cancer is pancreatic cancer.
 25. The compositionaccording to claim 19 wherein said cancer is pancreatic cancer.
 26. Thecomposition according to claim 18 which is in oral dosage form.
 27. Thecomposition according to claim 18 which is in parenteral dosage form.28. The composition according to claim 18, wherein the mammal is ahuman.
 29. The composition according to claim 19, wherein the mammal isa human.
 30. The composition according to claim 20, wherein the mammalis a human.
 31. The composition according to claim 21, wherein themammal is a human.
 32. A composition for use in inhibiting the growth ofa tumor comprising i) an anti-tumor effective amount of a herbalpreparation comprising Scutellaria, Glycyrrhiza, Ziziphus, and Paeonia;and ii) a chemotherapeutic formulation comprising an anti-tumoreffective amount of sorafenib, in combination with a pharmaceuticallyacceptable carrier, additive and/or excepient wherein said tumor is atumor of a gastrointestinal cancer.
 33. The composition according toclaim 32 wherein said gastrointestinal cancer is hepatocellular cancer,colorectal cancer or pancreatic cancer.
 34. The composition according toclaim 32 wherein said herbal preparation comprises Scutellariabaicalensis, Glycyrrhiza uralensis, Ziziphus jujuba, and Paeonialactiflora.
 35. The composition according to claim 33 wherein saidcancer is hepatocellular cancer.
 36. The composition according to claim34 wherein said cancer is hepatocellular cancer.
 37. The compositionaccording to claim 33 wherein said cancer is colorectal cancer.
 38. Thecomposition according to claim 34 wherein said cancer is colorectalcancer.
 41. The composition according to claim 34 wherein said cancer ispancreatic cancer.
 42. The composition according to claim 34 whereinsaid cancer is pancreatic cancer.
 43. The composition according to claim32 in oral dosage form.
 44. The composition according to claim 32 inparenteral dosage form.
 45. The composition according to claim 32,wherein the mammal is a human.
 46. The composition according to claim33, wherein the mammal is a human.
 47. The composition according toclaim 34, wherein the mammal is a human.
 48. The composition accordingto claim 35, wherein the mammal is a human.